Dual-functional composite scaffolds for inhibiting infection and promoting bone regeneration

Abstract

The treatment of infected bone defects is an intractable problem in orthopedics. It comprises two critical parts, namely that of infection control and bone defect repair. According to these two core tasks during treatment, the ideal approach of simultaneously controlling infection and repairing bone defects is promising treatment strategy. Several engineered biomaterials and drug delivery systems with dual functions of anti-bacterial action and ostogenesis-promotion have been developed and demonstrated excellent therapeutic effects. Compared with the conventional treatment method, the dual-functional composite scaffold can provide one-stage treatment avoiding multiple surgeries, thereby remarkably simplifying the treatment process and reducing the treatment time, overcoming the disadvantages of conventional bone transplantation. In this review, the impaired bone repair ability and its specific mechanisms in the microenvironment of pathogen infection and excessive inflammation were analyzed, providing a theoretical basis for the treatment of infectious bone defects. Furthermore, we discussed the composite dual-functional scaffold composed of a combination of antibacterial and osteogenic material. Finally, a series of advanced drug delivery systems with antibacterial and bone-promoting capabilities were summarized and discussed. This review provides a comprehensive understanding for the microenvironment of infectious bone defects and leading-edge design strategies for the antibacterial and bone-promoting dual-function scaffold, thus providing clinically significant treatment methods for infectious bone defects.

Keywords: Antibacterial; Bone repair; Dual-functional scaffold; Infectious bone defect.

Graphical abstract

Scheme 1

Various material-based and drug delivery system-based dual-functional scaffolds promote the repair of infectious bone defects by simultaneously inhibiting bacteria and promoting osteogenesis.

Fig. 1

Effect of local inflammation on osteogenesis: Osteogenesis is promoted by an appropriate inflammatory response due to local trauma (left); Chronic and excessive inflammation due to infection inhibits bone repair (right).

Fig. 2

Effect of infection on bone repair: A. Pathogens indirectly bind to cells through colonization onto the ECM, which can destroy ECM components and lead to the biofilm formation; B. Pathogens and their secreted soluble factors promote osteoblast apoptosis by binding to cell surface receptors; C. Pathogens infect osteoblasts with the participation of fibronectin and cytoskeletal components, and the internalized pathogens inhibit osteogenesis and maintain excessive inflammation; D. Infected osteoblasts, excessive inflammation, surface components, and secreted soluble factors of pathogens as well as immune complexes formed by pathogens promote osteoclastogenesis.

Fig. 3

HACC grafted HA/PLGA scaffold for the repair of infectious defects [117]: A. Schematic diagram of HACC grafted HA/PLGA scaffold (P/HA/H) and its experimental protocol; B. Bacterial culture of the screws and confocal microscope images of the biofilm on the surfaces of screws and the polyethylene plates after eight weeks of implantation of PLGA (P), PLGA/HA (P/HA), PLGA grafted with HACC (P/H), and P/HA/H into infected rat femoral defects fixed with polyethylene plates and stainless steel screws; C-D: Colony counts of infectious defects in rats and rabbits in each group after eight weeks of implantation; E-F: Histological analysis of infected bone defect in rats (E) and infected femoral condyle defect in rabbits (F) after scaffold implantation in each group (scale bar ​= ​2 ​mm). Reprinted with permission from Ref. [117]. Copyright 2018, Elsevier Ltd.

Fig. 4

Carboxymethyl chitosan/sodium alginate mixed scaffold (CMC/Alg) containing Cu nanoparticles (CMC/Alg/Cu) for antibiosis and osteogenesis [135]: A. Fabrication process of CMC/Alg/Cu; B. SEM images of CMC/Alg/Cu (a) and CMC/Alg (b); C. Expression of osteogenesis-related genes after 14-day culture of MC3T3-E1 cells with composite scaffolds; D. Micro-CT reconstruction image of new bone after implantation of MC3T3-E1 cell-loaded composite scaffold into infected muscle capsule of rat gluteus maximus. E. Colonies of S. aureus on the implant at two and four weeks after implantation; F-G: After implantation of two and four weeks, the result of (F) Giemsa staining for residual bacteria and (G) Masson's trichrome staining for new bone formation (scale bar ​= ​50 ​μm). Reprinted with permission from Ref. [135]. Copyright 2018, American Chemical Society.

Fig. 5

TiO₂ and dopamine-AgNP co-modified the Ti6Al4V scaffold with antibacterial and osteogenic functions [142]: A. Manufacturing process of composite coating scaffold; B. Effects of titanium alloy scaffold without surface treatment (TiS) and composite coated scaffold (TiS-M/Ag) on ALP activity of MG63 ​cells; C,D: Quantitative analysis (C) and staining (D) of calcium and collagen deposits by alizarin red and Sirius red staining after 28 days of coculture of MG63 ​cells with TiS and TiS-M/Ag scaffolds; E-F: Inhibition of TiS and TiS-M/Ag on S. aureus (E) and E. coli (F): live and dead staining of bacteria (a-b), the interaction between AgNP and bacteria (c-e) (carmine represented bacteria, purple represented AgNP, and yellow arrow represented pores on membrane). Reprinted with permission from Ref. [142]. Copyright 2016, American Chemical Society.

Fig. 6

Dual-function collagen scaffold incorporated with Cu-doped bioactive glass [143]: A. Alizarin red staining of MC3T3-E1 culturing with collagen scaffolds (Collagen) and collagen scaffolds containing 300%(w/w) bioactive glass (300% CuBG) (scale bar ​= ​1 ​mm); B. Promotion of collagen scaffolds containing different concentrations of BG (w/w) for the angiogenesis of chicken embryo model, in which VEGF was used as the control group; C-D: Inhibition of collagen scaffolds containing different concentrations of BG (w/w) for S. aureus. Reprinted with permission from Ref. [143]. Copyright 2019, Elsevier Ltd.

Fig. 7

Hinokitiol loaded nano-BG(nBG)/PEEK scaffold (dmBPC) [179]: A. SEM images of the macroporous PEEK (mPK) (a, d), macroporous nBG/PEEK (BPC) (b, e) and macro-microporous/nBG/PEEK (mBPC) (c, f); B. Confocal laser scanning microscope images of mBPC and dmBPC cultured with S. aureus for 24 ​h; C. Colony number of viable bacteria on the surface of mBPC and dmBPC after culturing with S. aureus; D. Effect of composite scaffolds on ALP enzyme activity of MC3T3-E1 cells; E-F: Statistical analysis (E) and images (F) of positive areas of BMP-2 immunohistochemical staining at 1 (a-d) and 3 (e-h) months after implantation of scaffold (a, e represent mPK; b, f represent BPC; c, g represent mBPC and d, h represent dmBPC) into the femur of a rabbit (scale bar ​= ​200 ​μm). Reprinted with permission from Ref. [179]. Copyright 2018, Elsevier Ltd.

Fig. 8

Individual and co-release profiles of vancomycin and BMP-2 [188]: A. Release profiles of vancomycin from magnesium–zinc–silicon carriers without pores (MZS) and nanoporous magnesium–zinc–silicon carriers (n-MZS); B. Release profiles of BMP-2 from MZS and n-MZS; C. Co-release profiles of vancomycin and BMP-2 from n-MZS. Reprinted with permission from Ref. [188]. Copyright, the authors, published by Dove Medical Press Ltd.

Fig. 9

LbL-coated PEEK composite scaffold loaded with BMP-2 and gentamicin for treatment of infected bone defect [203]: A. Schematic representation of antibacterial and osteogenic properties of composite scaffold in vivo and ideal dual drug release profile; B. External image and bacterial bioluminescence image at eight weeks after the implantation of uncoated scaffold (U), gentamicin-coated scaffold (G), and gentamicin-and BMP-2-coated scaffold (BG) into the rat tibial infected by bioluminescent S. aureus; C. μCT reconstruction images of infected tibial defects implanted with U, G, BG. Reprinted with permission from Ref. [203]. Copyright 2016, American Chemical Society.